tbuckley/cabot-search huggingface dataset:
Risk Stratification to Predict Renal Survival in Anti–Glomerular Basement Membrane Disease
Authors: Lauren Floyd, Sebastian Bate, Abdul Hadi Kafagi, Nina Brown, Jennifer Scott, Mukunthan Srikantharajah, Marek Myslivecek, Graeme Reid, Faten Aqeel, Doubravka Frausova, Marek Kollar, Phuong Le Kieu, Bilal Khurshid, Ajay Dhaygude, Vladimir Tesar, Stephen McAdoo, Mark A. Little, Duvuru Geetha, Silke R. Brix
Journal: Journal of the American Society of Nephrology (2022)

Background Prospective randomized trials investigating treatments and outcomes in anti–glomerular basement membrane (anti-GBM) disease are sparse, and validated tools to aid prognostication or management are lacking. Methods In a retrospective, multicenter, international cohort study, we investigated clinical and histologic parameters predicting kidney outcome and sought to identify patients who benefit from rescue immunosuppressive therapy. We also explored applying the concept of the renal risk score (RRS), currently used to predict renal outcomes in ANCA-associated vasculitis, to anti-GBM disease. Results The final analysis included 174 patients (out of a total of 191). Using Cox and Kaplan–Meier methods, we found that the RRS was a strong predictor for ESKD. The 36-month renal survival was 100%, 62.4%, and 20.7% in the low-risk, moderate-risk, and high-risk groups, respectively. The need for renal replacement therapy (RRT) at diagnosis and the percentage of normal glomeruli in the biopsy were independent predictors of ESKD. The best predictor for renal recovery was the percentage of normal glomeruli, with a cut point of 10% normal glomeruli providing good stratification. A model with the predictors RRT and normal glomeruli ( N ) achieved superior discrimination for significant differences in renal survival. Dividing patients into four risk groups led to a 36-month renal survival of 96.4% (no RRT, N ≥10%), 74.0% (no RRT, N &lt;10%), 42.3% (RRT, N ≥10%), and 14.1% (RRT, N &lt;10%), respectively. Conclusions These findings demonstrate that the RRS concept is transferrable to anti-GBM disease. Stratifying patients according to the need for RRT at diagnosis and renal histology improves prediction, highlighting the importance of normal glomeruli. Such stratification may assist in the management of anti-GBM disease.
Bronchoscopic Lung Volume Reduction Complicated by Electrical Alternans
Authors: Kurt Hu, Elise M. Jondall, Jonathan S. Kurman, Bryan S. Benn
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Bronchoscopic Lung Volume Reduction Complicated by Electrical Alternans." American Journal of Respiratory and Critical Care Medicine, 207(7), pp. e69–e70
Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes
Authors: Ram Prasad, Jason L. Floyd, Mariana Dupont, Angela Harbour, Yvonne Adu-Agyeiwaah, Bright Asare-Bediako, Dibyendu Chakraborty, Kara Kichler, Aayush Rohella, Sergio Li Calzi, Regina Lammendella, Justin Wright, Michael E. Boulton, Gavin Y. Oudit, Mohan K. Raizada, Bruce R. Stevens, Qiuhong Li, Maria B. Grant
Journal: Circulation Research (2022)

Background: We examined components of systemic and intestinal renin-angiotensin system on gut barrier permeability, glucose homeostasis, systemic inflammation, and progression of diabetic retinopathy (DR) in human subjects and mice with type 1 diabetes (T1D). Methods: T1D individual with (n=18) and without (n=20) DR and controls (n=34) were examined for changes in gut-regulated components of the immune system, gut leakage markers (FABP2 [fatty acid binding protein 2] and peptidoglycan), and Ang II (angiotensin II); Akita mice were orally administered a Lactobacillus paracasei (LP) probiotic expressing humanized ACE2 (angiotensin-converting enzyme 2) protein (LP-ACE2) as either a prevention or an intervention. Akita mice with genetic overexpression of humanAce2 by small intestine epithelial cells ( Vil-Cre.hAce2KI-Akita ) were similarly examined. After 9 months of T1D, circulatory, enteral, and ocular end points were assessed. Results: T1D subjects exhibit elevations in gut-derived circulating immune cells (ILC1 cells) and higher gut leakage markers, which were positively correlated with plasma Ang II and DR severity. The LP-ACE2 prevention cohort and genetic overexpression of intestinal ACE2 preserved barrier integrity, reduced inflammatory response, improved hyperglycemia, and delayed development of DR. Improvements in glucose homeostasis were due to intestinal MasR activation, resulting in a GSK-3β (glycogen synthase kinase-3 beta)/c-Myc (cellular myelocytomatosis oncogene)-mediated decrease in intestinal glucose transporter expression. In the LP-ACE2 intervention cohort, gut barrier integrity was improved and DR reversed, but no improvement in hyperglycemia was observed. These data support that the beneficial effects of LP-ACE2 on DR are due to the action of ACE2, not improved glucose homeostasis. Conclusions: Dysregulated systemic and intestinal renin-angiotensin system was associated with worsening gut barrier permeability, gut-derived immune cell activation, systemic inflammation, and progression of DR in human subjects. In Akita mice, maintaining intestinal ACE2 expression prevented and reversed DR, emphasizing the multifaceted role of the intestinal renin-angiotensin system in diabetes and DR.
Body mass index and molecular subtypes of colorectal cancer
Authors: Neil Murphy, Christina C Newton, Mingyang Song, Nikos Papadimitriou, Michael Hoffmeister, Amanda I Phipps, Tabitha A Harrison, Polly A Newcomb, Elom K Aglago, Sonja I Berndt, Hermann Brenner, Daniel D Buchanan, Yin Cao, Andrew T Chan, Xuechen Chen, Iona Cheng, Jenny Chang-Claude, Niki Dimou, David Drew, Alton B Farris, Amy J French, Steven Gallinger, Peter Georgeson, Marios Giannakis, Graham G Giles, Stephen B Gruber, Sophia Harlid, Li Hsu, Wen-Yi Huang, Mark A Jenkins, Ruhina S Laskar, Loic Le Marchand, Paul Limburg, Yi Lin, Marko Mandic, Johnathan A Nowak, Mereia Obón-Santacana, Shuji Ogino, Conghui Qu, Lori C Sakoda, Robert E Schoen, Melissa C Southey, Zsofia K Stadler, Robert S Steinfelder, Wei Sun, Stephen N Thibodeau, Amanda E Toland, Quang M Trinh, Kostas K Tsilidis, Tomotaka Ugai, Bethany Van Guelpen, Xiaoliang Wang, Michael O Woods, Syed H Zaidi, Marc J Gunter, Ulrike Peters, Peter T Campbell
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Background Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease. Methods We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables. Results Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control). Conclusions In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome.
Comparison of Lobectomy vs Total Thyroidectomy for Intermediate-Risk Papillary Thyroid Carcinoma With Lymph Node Metastasis
Authors: Siyuan Xu, Hui Huang, Ying Huang, Jiaxin Qian, Xiaolei Wang, Zhengang Xu, Shaoyan Liu, Jie Liu
Journal: JAMA Surgery (2022)

Surgical treatment of patients with papillary thyroid cancer (PTC) by either lobectomy or total thyroidectomy (TT) has long been a topic of debate, especially for patients with intermediate-risk PTC.To compare recurrence-free survival (RFS) for patients with PTC and lymph node metastasis after lobectomy vs TT.This retrospective cohort study included a review of patients with PTC treated from January 1, 2000, to December 31, 2017. Propensity score matching (PSM) was performed between patients treated with lobectomy and TT. This study involved a single institute in a cancer referral center. Enrolled were adult patients (aged 18-75 years) with unilateral PTC and ipsilateral clinical lateral neck metastasis (cN1b). Patients with the following characteristics were excluded: a lymph node yield less than 20, primary tumor size greater than 4 cm, gross extrathyroidal extension, metastatic lymph node size greater than 3 cm, and distant metastasis. Data analysis was performed from April 1 to April 30, 2022.Lobectomy and TT.The primary outcome was the association between extent of surgery and RFS, assessed using Cox proportional hazards regression models.A total of 946 patients with PTC (mean [SD] age, 37.0 [12.1] years, 630 female individuals [66.6%]) were analyzed. Lobectomy (624 [66.0%]) was negatively correlated with the frequencies of older age (≥65 years, 17 [2.7%]), female sex (393 [63.0%]), multifocality (132 [21.2%]), minor extrathyroidal extension (259 [41.5%]), number of metastatic lymph nodes (median [range], 9 [6-14] nodes), and radioactive iodine ablation (0). After PSM with treatment period and potential prognostic factors (age, sex, primary tumor size, multifocality, minor extrathyroidal extension, number of lymph node metastases and lymph node ratio), 265 pairs of patients were available for analysis. After a median (range) follow-up of 60 (9-150) months in the lobectomy group and 58 (8-161) months in the TT group, 21 (7.9%) and 17 (6.4%) structural recurrences were identified in the lobectomy and TT groups, respectively. Lobectomy was not associated with significantly compromised 5-year RFS rate (lobectomy, 92.3% vs TT, 93.7%; adjusted hazard ratio, 1.10; 95% CI, 0.58-2.11; P = .77). Power analysis indicated that the test had 90% power to detect a more than 4.9% RFS difference. No significant difference in RFS was observed between patients treated with TT and radioactive iodine ablation (n = 75) and their counterparts (adjusted hazard ratio, 0.59; 95% CI, 0.14-2.41; P = .46).Results of this cohort study suggest that patients with PTC and lymph node metastasis had a similar RFS after lobectomy vs those who had TT. If radioactive iodine ablation is not going to be performed, lobectomy may be an effective alternative option.
Nudging to Improve Cardiovascular Care—Clinicians, Patients, or Both
Authors: Faraz S. Ahmad, Stephen D. Persell
Journal: JAMA Cardiology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Acneiform Eruption Following Elexacaftor-Tezacaftor-Ivacaftor Treatment in Patients With Cystic Fibrosis
Authors: Léa Okroglic, Pierre Sohier, Clémence Martin, Coralie Lheure, Nathalie Franck, Isabelle Honoré, Reem Kanaan, Pierre-Régis Burgel, Agnès Carlotti, Nicolas Dupin, Bénédicte Oulès
Journal: JAMA Dermatology (2022)

A new treatment for cystic fibrosis combining 3 CFTR modulators-elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA)-has recently been approved for cystic fibrosis treatment. The cutaneous adverse effects following treatment with this combination are poorly described in the literature.
Lipid nanoparticles for delivery of RNA therapeutics: Current status and the role of <i>in vivo</i> imaging
Authors: Han Na Jung, Seok-Yong Lee, Somin Lee, Hyewon Youn, Hyung-Jun Im
Journal: Theranostics (2022)

Lipid nanoparticles (LNPs) have been one of the most successful nano-delivery vehicles that enable efficient delivery of cytotoxic chemotherapy agents, antibiotics, and nucleic acid therapeutics.During the coronavirus disease (COVID-19) pandemic, LNP-based COVID-19 messenger RNA (mRNA) vaccines from Pfizer/BioNTech and Moderna have been successfully developed, resulting in global sales of $37 billion and $17.7 billion, respectively, in 2021.Based on this success, the development of multiple LNP-based RNA therapeutics is gaining momentum due to its potential in vaccines and therapeutics for various genetic diseases and cancers.Furthermore, imaging techniques can be utilized to evaluate the pharmacokinetics and pharmacodynamics (PK/PD) effects, which helps target discovery and accelerates the development of LNP-based mRNA therapies.A thorough introduction and explanation of the components of LNPs and its functions along with various production methods of formulating LNPs are provided in this review.Furthermore, recent advances in LNP-based RNA therapeutics in clinics and clinical trials are explored.Additionally, the evaluation of PK/PD of LNPs for RNA delivery and the current and potential roles in developing LNP-based mRNA pharmaceutics through imaging techniques will be discussed.
Delivery of Induced Neural Stem Cells Through Mechano‐Tuned Silk–Collagen Hydrogels for the Recovery of Contused Spinal Cord in Rats
Authors: Ganchimeg Davaa, Jin Young Hong, Jung‐Hwan Lee, Min Soo Kim, Jennifer O. Buitrago, Yu‐Meng Li, Hae‐Hyoung Lee, Dong Wook Han, Kam W. Leong, Jung Keun Hyun, Hae‐Won Kim
Journal: Advanced Healthcare Materials (2022)

Neural stem cells (NSC) have tremendous potential for therapeutic regeneration of diseased or traumatized neural tissues, including injured spinal cord. However, transplanted NSC suffer from low cell survival and uncontrolled differentiation, limiting in vivo efficacy. Here, this issue is tackled by delivery through silk-collagen protein hydrogels that are stiffness-matched, stress-relaxing, and shear-thinning. The mechanically-tuned hydrogels protect NSC reprogrammed from fibroblasts (iNSC) initially from injection shear-stress, and enhance long-term survival over 12 weeks. Hydrogel-iNSC treatment alleviates neural inflammation, with reduced inflammatory cells and lesions than NSC-only. The iNSC migrate from the hydrogel into surrounding tissues, secrete up-regulated neurotrophic factors, and differentiate into neural cell subtypes, forming synapses. More serotonergic axons are observed in the lesion cavity, and locomotor functions are improved in hydrogel-iNSC than in iNSC-only. This study highlights the ability of mechanically-tuned protein hydrogels to protect iNSC from the injection stress and severe inflammatory environment, allowing them to differentiate and function to recover the injured spinal cord.
Commensal gut microbiota-derived acetate and propionate enhance heart adaptation in response to cardiac pressure overload in mice
Authors: Chen-Ju Lin, Yu-Che Cheng, Hung-Chih Chen, Yu-Kai Chao, Martin W Nicholson, Eric C L Yen, Timothy J Kamp, Patrick C H Hsieh
Journal: Theranostics (2022)

Background: The gut microbiota plays a vital role in maintaining tissue homeostasis and regulating disease pathophysiology; however, the underlying mechanisms remain to be elucidated. We previously showed that mice depleted of gut microbiota with antibiotics (ABX mice) were more prone to cardiac rupture after infarction, suggesting that the gut microbiota impacts cardiac structural remodeling following injury. Here, we aimed to determine whether the gut microbiota is required for adaptive cardiac remodeling in response to pressure overload stress. Methods: Transverse aortic constriction (TAC) surgery was performed and cardiac function was evaluated by echocardiography and catheterization, followed by mechanical tests and extracellular matrix (ECM) studies. Germ-free mice with cecal microbiota transplantation were used for validation. 16S ribosomal DNA sequencing and PICRUSt2 analysis were applied to predict the key metabolic pathways. ABX mice were supplemented with the derived metabolic products and their efficacy was tested. To elucidate the underlying mechanism, we isolated mouse primary cardiac fibroblasts and treated them with the metabolites. Lastly, G-coupled protein receptor 41 (GPR41) and GPR43 double knockdown cardiac fibroblasts were generated and the anti-fibrogenic effect of metabolites was determined. Results: Cardiac hypertrophy and dysfunction were more severe in ABX-TAC mice compared to the controls. Moreover, TAC-induced fibrosis was more profound in ABX hearts, which was accompanied by disrupted ECM structure making the heart tissues mechanically weaker and more brittle. Reconstruction of healthy gut microbiota in germ-free mice successfully restored cardiac function and prevented excessive fibrosis and ECM disarray under stress. Furthermore, functional prediction identified acetate and propionate as critical mediators in the gut microbiota-modulated cardiac mechanics. Supplementation of acetate and propionate improved heart function, attenuated fibrosis, and reversed ECM disarray after TAC. In addition, treating primary cardiac fibroblasts with acetate and propionate attenuated cell contraction, inhibited myofibroblast formation, and reduced collagen formation after TGF-β1 stimulus. Finally, knocking down GPR41 and GPR43 receptors in cardiac fibroblasts blunted the inhibitory effects of acetate and propionate. Conclusions: The gut microbiota is a potential therapeutic target for cardiac ECM remodeling and heart structural integrity. By establishing a healthy gut microbiome or replenishing the derived metabolites, we could improve cardiac health under dysbiosis after pressure-overload stress.
Enhancer reprogramming promotes the activation of cancer-associated fibroblasts and breast cancer metastasis
Authors: Qian Li, Xuejiao Lv, Chunyong Han, Yu Kong, Zhongye Dai, Dawei Huo, Ting Li, Dapeng Li, Wei Li, Xing Wang, Qian Zhao, Jie Ming, Wen Yang, Yang Chen, Xudong Wu
Journal: Theranostics (2022)

Rationale: Cancer associated fibroblasts (CAFs) are a subpopulation of cells within the tumor microenvironment that usually promote cancer progression and metastasis. Hence it is critical to find out the driving factors and mechanisms for the development of CAFs from normal fibroblasts (NFs) in response to sustained stimulation of cancer cells. Here we perform transcriptomic and epigenomic analyses in paired NFs and CAFs associated with breast cancer metastasis to investigate the molecular mechanisms for stromal fibroblasts reprogramming. Methods: We conducted transcriptomic analyses in paired NFs and CAFs isolated from clinical specimens of breast cancer patients with metastasis. Meanwhile, genome-wide mapping of histone marks H3K4me1 and H3K27ac was also performed to characterize CAF-specific enhancer landscape. The function and mechanisms of activated JUN in stromal fibroblasts were studied using in vitro and in vivo models. Results: We have identified CAF-specific signature genes and activated enhancers, which are significantly associated with pro-metastatic programs. Among the CAF activated enhancers, FOS and JUN family of transcription factors are enriched. In line with this, we find that JUN protein is highly activated in the stroma of metastatic breast cancers. And through gain and loss-of-function studies, we demonstrate that activated JUN is necessary and sufficient to remodel enhancers and maintain the activation of CAF-specific enhancers, and thereby promotes breast cancer invasiveness in a non-cell-autonomous manner. Conclusions: Our study gets an insight into the transcriptomic features of invasive breast stroma and transcription regulatory mechanisms for stroma cell transformation, providing a proof-of-concept of stroma-targeting strategy in cancer treatment.
Necroptosis-dependent Immunogenicity of Cisplatin: Implications for Enhancing the Radiation-induced Abscopal Effect
Authors: Ren Luo, Kateryna Onyshchenko, Liqun Wang, Simone Gaedicke, Anca-Ligia Grosu, Elke Firat, Gabriele Niedermann
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Cisplatin is increasingly used in chemoimmunotherapy and may enhance the T cell–dependent radiation-induced abscopal effect, but how it promotes antitumor immunity is poorly understood. We investigated whether and why cisplatin is immunogenic, and the implications for the cisplatin-enhanced abscopal effect. Experimental Design: Cisplatin, carboplatin, and the well-known immunogenic cell death (ICD) inducer oxaliplatin were compared for their potency to enhance the abscopal effect and induce type I IFN (IFN-I) and extracellular ATP, danger signals of ICD. The hypothetical role of necroptosis and associated damage-associated molecular patterns for cisplatin-induced ICD was investigated by inhibitors and knockout cells in vitro and in two tumor models in mice. A novel necroptosis signature for tumor immune cell infiltration and therapy response was developed. Results: Cisplatin enhanced the abscopal effect more strongly than oxaliplatin or carboplatin. This correlated with higher induction of IFN-I and extracellular ATP by cisplatin, in a necroptosis-dependent manner. Cisplatin triggered receptor-interacting protein kinase 3 (RIPK3)-dependent tumor cell necroptosis causing cytosolic mitochondrial DNA (mtDNA) release, initiating the cyclic GMP–AMP synthase–stimulator of interferon genes pathway and IFN-I secretion promoting T-cell cross-priming by dendritic cells (DC). Accordingly, tumor cell RIPK3 or mtDNA deficiency and loss of IFN-I or ATP signaling diminished the cisplatin-enhanced abscopal effect. Cisplatin-treated tumor cells were immunogenic in vaccination experiments, depending on RIPK3 and mtDNA. In human tumor transcriptome analysis, necroptotic features correlated with abundant CD8+ T cells/DCs, sparse immunosuppressive cells, and immunotherapy response. Conclusions: Cisplatin induces antitumor immunity through necroptosis-mediated ICD. Our findings may help explain the benefits of cisplatin in chemo(radio)immunotherapies and develop clinical trials to investigate whether cisplatin enhances the abscopal effect in patients.